Drug resistance remains one of the major obstacles in treatment of patients with various types of cancer, including multiple myeloma (MM). Evidence accumulated for the past decade has indicated a prominent role of microenvironment in survival and growth of tumor cells. Focusing on MM we have recently demonstrated that microenvironment, particularly bone marrow stromal cells, has a significant impact on the response of tumor cells to the chemotherapy. Bone marrow stroma protected myeloma cells from initial treatment with cytotoxic drugs. Allowing surviving a subpopulation of tumor cells, bone marrow stroma thus may contribute to the development of minimal residual disease and eventually clinical relapse. Our previous work has indicated that one of the mechanisms of this bone marrow stroma mediated drug-resistance is activation of receptor/transcriptional regulator Notch in MM cells. The overall hypothesis of this application is that tumor microenvironment activates Notch signaling in MM cells allowing them to escape drug-induced cell death. Pharmacological inhibition of Notch reverses this effect and therefore may be therapeutically beneficial for patients with MM. In this proposal, we will investigate the molecular mechanisms of Notch mediated MM cell protection from apoptosis induced by chemotherapeutic drugs and possible approaches to overcome it. The overall goal of the proposal is to develop a new therapeutic approach based on inhibition of Notch signaling. Specific aims of the project: Aim 1. Investigate the involvement of different Notch family members and ligands in MM cell drug resistance; Aim 2. Examine the contribution of Notch signaling to integrin mediated drug resistance in MM cells; Aim 3. Study the effect of hypoxia on Notch signaling and drug resistance in MM cells; and Aim 4. Evaluate the therapeutic potential of Notch inhibitor in combination with Bcl-2/Bcl-xL inhibitor ABT-737 in treatment of MM. Drug resistance is one of the major obstacles in treatment of patients with different types of cancer, including multiple myeloma.